Basic phenoxy acetamides



United States Patent Oflice Patented Dec. 29, 1970 1m. 01. cine 103/22US. Cl. 260-472 6 Claims ABSTRACT OF THE DISCLOSURE Thedialkylaminoalkyl esters of para (phenoxyacetamido)benzoic acidscorresponding to the formula in which R is a hydrogen or halogen atom ora lower alkyl, lower alkenyl, phenyl, phenylalkyl, hydroxyl, alkoxy,alkenoxy, cycloalkoxy, phenylalkoxy, acyl, nitro, amino or sulphamylgroup, -R is a hydrogen or halogen atom or a lower alkyl, phenyl,phenylalkyl, alkoxy or lower acyl group, R is a hydrogen atom, a loweralkyl, trifiuoromethyl or alkoxy group, R is a hydrogen atom or an alkylgroup, X is a methylene group which may be substituted by one or twoalkyl groups or by a phenyl group and Y is a group having the formula inwhich n is 2 or 3 and each of R and R is a lower alkyl group or R and Rtaken together with the nitrogen atom to which they are attached form aheterocyclic group which may contain a nuclear oxygen atom, providedthat when R is a halogen atom and R is a hydrogen atom the methylenegroup X has less than two substituents, and the addition salts of suchesters with acids, are provided. The esters are used in the treatment ofpathological states relating to lipid metabolism.

This invention relates to para(phenoxyacetamido)- benzoic acid esters ofdialkylaminoalkanols which may contain substituents in the phenoxy groupand to a process for the preparation thereof.

It is known that diethylaminoethyl para-aminobenzoate has the propertyof stimulating cellular respiration (A. Aslan, Arzneimittelforschung1958, page 11). It is also known that this activity can be increased bycombining the free amine group with nicotinic acid to form an amidefunction (K/L Zirm and A. Pongratz, Arzneimittelforschung 1960, page412).

It is also known that certain derivatives of phenoxyacetic acids have animportant effect on the lipid metabolism of man.

The present invention has been conceived with a view to providingcompounds which have within their structure the characteristics of thediethylaminoethyl paraamino-benzoate molecule and of the phenoxyaceticacids and which also have a favourable action on cellular respiration,tissue respiration and lipid metabolism.

In accordance with the present invention there is provided apara(phenoxyacetamido)benzoic acid ester of a dialkylaminoalkanol havingthe general formula in which R is a hydrogen or halogen atom or a loweralkyl, lower alkenyl, phenyl, phenylalkyl, hydroxyl, alkoxy, alkenoxy,cycloalkoxy, phenylalkoxy, acyl, nitro, amino or sulphamyl group, R is ahydrogen or halogen atom or a lower alkyl, phenyl, phenylalkyl, alkoxyor lower acyl group, R is a hydrogen atom, a lower alkyl,trifiuoromethyl or alkoxy group, R is a hydrogen atom or an alkyl group,X is a methylene group which may be substituted by one or two alkylgroups or by a phenyl group and Y is a group having the formula in whichn is 2 or 3 and each of R and R is a lower alkyl group or R and R takentogether with the nitrogen atom to which they are attached form aheterocyclic group which may contain a nuclear oxygen atom, providedthat when R is a halogen atom and R is hydrogen the group X has not morethan one substituent, and the addition salts of such esters with acids.

The present invention also provides a process for the preparation of thehydrohalides of a para(phenoxyacetamido)benzoic acid ester of adialkylaminoalkanol having the general formula in which R R R R and Yare as above defined, which comprises reacting a para arninobenzoic acidester having the general formula in which Y is as above defined, with aphenoxyacyl halide having the general formula in which R R R R and X areas above defined and Hal is a halogen atom.

The acid chlorides used as starting materials in this process may beprepared by a conventional method, in particular by the action ofthionyl chloride upon a suitable acid in an inert solvent such asbenzene; they are isolated by distillation and are used as such.

The acids from which the acid chlorides mentioned above are obtained maybe prepared by the condensation of phenols having the substituents R R Rand R either (a) with an alkyl ester, more especialy a lower alkyl esterof a-bromoacetic, a-bromobutyric, a-bromoisobutyric, a-bromopropionic,a-bromoisovaleric or ocbromophenylacetic acid, the ester obtained by thecondensation being saponified in a separate step to yield thecorresponding acid; or (b) when X is the divalent group -C(CH withacetone and chloroform in the presence of powdered soda.

A number of the acid starting materials prepared in this way are notrecorded in the chemical literature; they are set out in Table I below;M.P. indicates the melting point measured on the Kofler bench and MP.indicates the melting point measured in a capillary tube withoutcorrection.

TABLE I I O R? Melting point and Letter of crystallisation identi- R R Xsolvent, C. fication Cl Cl CH(C H M.P.K 136-137" A (benzene). IsopropoxyH C(CHa): M.P. 57 (light 13 petroleum). n-Butoxy H C(CHm C petroleum).n-Peutyloxy II CH2 Ml .c 115 (diiso- D propyl ether). D II CII(CglI1\l.1.c 58 (light E petroleum).

Do II C(CIIz): 111.1.c 73 (light; F

v petroleum). ullexyloxy 11 (III: 1\l.l. 114 (benezene). (wCyclopentyloxy II C((Jll h M.P.K 100 (diiso- Ii propyl ether).llcuzyloxy II C(CIIm M.l.K 3 17 (diiso- I propyl ether).

The reaction of the acid chlorides with the amino esters and inparticular with Z-diethylaminoethyl paraaminobenzoate is preferablycarried out in an anhydrous diluent which is inert to the compoundsused, for example a hydrocarbon such as benzene or better still a ketonesuch as acetone, at a temperature which may vary from room temperatureto the boiling point of the diluent. The corresponding amide is obtainedin the form of its hydrochloride which in many cases crystallises outdirectly. If this is not the case, it is advantageous for the purpose ofpreparing a crystalline salt to decompose the hydrochloride in aqueoussolution with an alkaline agent such as sodium carbonate, extract thebase liberated with a suitable solvent such as diethyl ether or ethylacetate, evaporate the solvent and treat the residue with a suitablemineral or organic acid such as hydrochloric acid, fumaric acid oroxalic acid in equimolecular quantity. The salts may be purified byrecrystallization. The corresponding bases have been obtained in thecrystalline state in a large number of cases.

To prepare the 4-(para-amino-phenoxyacetylamino) benzoates of thedialkylaminoalkanols, especially of 2- diethylaminoethanol or compound4415 CB, it is preferred to reduce the corresponding nitro compound byone of the conventional methods to the amino compound, for example usingiron, zinc or tin in an acid medium or using stannous chloride or in thepresence of a catalyst (in particular palladium carbon) in a solventsuch as ethyl alcohol.

The products shown in Table II hereinafter have been prepared in theform of salts and bases. They have been fully identified by elementaryanalysis and infra-red spectography with a Unicam S.P. 200 instrument.

In solution in methylene chloride, the bases show, among others, a bandat 3400 cm.- (N-H), a wide, intense band around 1700 cm." (merged bandsof amide I and ester), a double band in the region of 1600 cm.- and theamide II band in the region of 1530 cm.- The salts in some cases havecertain additional features; thus it has been found that thehydrochloride of the compound of Example 2 (compound 2842 CB) can existin two isomeric crystalline forms of identical melting point (the sameas their mixture), the formation of which is related to thecrystallisation time. The crystalline forms are distinguished by theirinfra-red spectra (in potassium brobide): Among other things, as regardsthe 0 0 bond, one of the forms (No. 1) has a wide band around 1710 cm.whereas the second form has two distinct bands, one around 1710 cm.- andthe other around 1680 cm.- One can pass from one to the other formaccording to whether separation of the crystalline product from itsmother liquor is carried out rapidly (first form) or slowly (secondform).

The observations made on one and the other of the two forms of compound2842 CB or their mixture concerning the C O bands apply similarly to theother hydrochlorides.

The fumarates and oxalates have, among other things, a more or less wideand often complex band between 1680 and 1700cm.-

In the following preparations and examples, the melting points aredetermined either upon the Kofler bench (M.P. or in a capillary tube andare uncorrected (M.P. unless otherwise indicated. The products described(salts and bases) were subjected to elementary analysis of all theirelements. In all cases, the values found agreed with the formulae given.

Preparation of carboxylic acids shown in Table l.

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0mg 26 00 m m m OOQH OO m 0m 0 600 0.00 0 .2: 002 B2 0.3 093 000 0 iOOJH m m n GHOQH 28 .0 0 9.52 fiwmwm 1.15. 1... IQENOVEO H m U oinm wmAmofim n v 0 ownfi :KHAZ 420E 0202 30 0 .2 0 2 mv nnunnnnnn hu unun X 00 m 0 I005 g 6650300308 0 2: 02 02mm 0 QHD i m E Ofl mm 6650308030 0 0102 02m 0 0 m W W AEOV EW MM 00 05 I. 0| wwmsmmzo 00 0E000 m m m mo m O0m QHOaH 28 .0 OF: E mw 3 00 250 m m 7 QHQ MU 0 O nwwmmfimww I50 m m A 20 0 .2: 0 2 0am 2 0 =0 {001... QEOVMO I m 0233 2 0 D00 02 m .601... mmwW M .GHOAMC .0 0mm MKHE 3 50 3 2 5000 38 0 0 2 00.0.2 fi iw fim mwmwi... QEOVEO m 0 m0 mm 5:005 0088 0 E 500 55 250 20 S P03332550 um m M "m5H 0:009:00 Q Z 9 PREPARATION (4-n-pentyloxy-phenoxy) acetic acid(compound D) i 6 hours. The mineral precipitate is then separated bysuction filtration, the filtrate evaporated to dryness and the residuetreated with ,water and ether. The ethereal phase is separated, washedwith a dilute soda solution and then with water, and dried over sodiumsulphate. The solvent is evaporated and the residue distilled at 180 to185 C. (temperature of water bath) under 0.1 mm. of mercury. The ethylester of 4-(n-pentyloxy)phenoxyacetic acid is thus obtanied.

50 ml. of ethanol and a solution of 6.8 g. of potassium hydroxide in 120ml. of water are added to 16 g. of this ester and the reaction mixtureis then heated under reflux for 2 hours. When the operation is complete,the solvent is evaporated, the residue diluted with water and theaqueous solution thus formed acidified with a suflicient quantity ofhydrochloric acid. 4-(n-pentyloxy)phenoxyacetic acid precipitates in thecrystalline state. It is recrystallised frorn diisopropyl ether, M.P.=115 C.

Acids A and G set out in Table I can be prepared by the same procedure,but to obtain compound G ethyl bromoacetate is replaced by an equimolarproportion of ethyl a-bromo-phenylacetate.

PREPARATION 2 -(n-butoxy)phenoxy-isobutyric acid (compound C) 24 g. ofpowdered sodium carbonate are added to a solution of 16.6 g. of4-n-butoxyphenol in 125 ml. of acetone whilst the reaction mixture iscooled to room temperature, and 18 g. of chloroform are then addedwhilst the temperature of the mixture is kept at 18 to C. The additionof chloroform, which gives rise to an exothermic reaction, requires 90minutes. When the evolution of heat has subsided, the reaction mixtureis heated under reflux for 4 hours while stirring is continued. Thesolvent is then evaporated, the residue treated with water, theinsoluble material extracted with diethyl ether, and the aqueous layerseparated and acidified with hydrochloric acid, which precipitates thedesired acid in the crude state. To purify this acid, it is dissolved indiethyl ether and the purified acid is extracted with a solution ofpotassium carbonate. The aqueous phase is separated and acidified withhydrochloric acid. The product is separated by suction filtration andrecrystallised from light petroleum. M.P. =76 C.

The acids B, E, F, H and I are similarly prepared.

The acid chlorides may be prepared in particular by the action ofthionyl chloride on the carboxylic acids. An example is given below.

PREPARATION 3 (4-n-butoxy-phenoxy)-isobutyric acid chloride 12 g. of(4-n-butoxy-phenoxy)-isobutyric acid in ml. of benzene are heated underreflux for 2 hours with 7.2 g. of thionyl chloride. When the operationis finished, the solvent is evaporated on a water bath under the reducedpressure produced by a filter pump and the residue distilled at 145 C.(temperature of the heating bath) under 0.1 mm. of mercury.

Prepaartion of the products set out in Table II.The reaction of the acidchlorides with the dialkylarninoalkyl para-aminobenzoates (in particularwith Z-diethylaminoethyl para-aminobenzoate) is best carried out inacetone (compound Other solvents, however, may also be used; thus oneexample is given in which benzene is used (compound 3).

1 0 EXAMPLE 1 Diethylaminoethyl 4-[ 4'-cyclopentyloxy-phenoxy-isobutyrylamino] benzoate (compound 50 or 4636 CB) 8.6 g. ofZ-diethylaminoethyl para-aminobenzoate dissolved in 40 ml. of acetoneare added to a solution of 10.3 g. of (4-cyclopentyloxyphenoxy) acetylchloride in ml. of acetone. The reaction is marked by a rise intemperature which heats the solvent to near its boiling point. Oncooling to room temperature, the solution deposits 11 g. of whitecrystals, M.P. =l34 C. When recrystallised from acetone, the crystalsmelt at 134-135 0.; they consist of the hydrochloride of the compound.

To prepare the corresponding base, the hydrochloride is dissolved inwater, and diethyl ether and a suflicient quantity of an aqueous sodiumcarbonate solution are added. After the ethereal solution has beenseparated and dried over sodium sulphate and the solvent evaporated, awhite crystalline product is obtained which is easily recrystallisedfrom diisopropyl ether. The base is thereby obtained (M.P. =104-l0S 0).

EXAMPLE 2 Diethylaminoethyl 4-[ 4'-chloro-phenoxy -acetylamino] benzoate(compound 3 or 2842 CB) 5.6 g. of 2-diethylaminoethyl para-aminobenzoatedissolved in ml. of benzene are added to a solution of 4.9 g. of 4-choro-phenoxyacetyl chloride in 10 ml. of benzene. The heat evolved causesthe benzene to reflux. The hydrochloride of the compound crystallises oncooling. It is recrystallised from 96% ethyl alcohol. 9.5 g. areobtained, M.P. =172 c.

The corresponding base, prepared as described in the preceding example,melts at 131 C. after crystallisation from ethanol. 1

All the compounds enumerated in Table II (with the exception of compound58) are prepared by the procedure given above for compound 50. In eachcase, the appropriate acid chloride is used which is reacted with the2-diethylaminoethyl para-aminobenzoate with the exception of compounds6, 7, 8, 9, and 10 for which the 2-diethylaminoethyl ester is replaced,respectively by the paraaminobenzoates of:

2-di-isopropylaminoethanol (compound 6) 3-dimethylamino n-propanol(compound 7) Z-dimethylamino-l-methylethanol (compound 8)2-piperidinoethanol (compound 9) 2-morpholinoethanol (compound 10) Fouradditional Examples (3 to 6) are given below further to illustrate theprocedure already used in Example 1.

EXAMPLE 3 Diethylaminoethyl4-[2'-4"-chloro-phenoxy)-butyrylamino]benzoate (compound 5 or 4409 CB) Asolution of 23 g. of Z-diethylaminoethyl para-aminobenzoate in ml. ofacetone are added to a solution of 22.4 g. of2-(4'-chlorophenoxy)-butyryl chloride in ml. of acetone. The reaction isexothermic. After a few minutes the reaction mixture is evaporated underreduced pressure and the residue, which consists of the hydrochloride ofcompound 4409 CB in the oily state, is decomposed. This is carried outas described above in Example 1. The base is obtained in the oily state;it is dissolved in acetone and treated with an equimolecular quantity ofoxalic acid. 48 g. of the acid oxalate is obtained which isrecrystallised from 90% ethanol.

EXAMPLE 4 Diethylaminoethyl4-[(2,4-dichloro-phenoxy)acetylaminoJbenzoate (compound 11 or 4407 CB) Asolution of 34.7 g. of 2-diethylaminoethyl paraaminobenzoate in ml. ofacetone is added to a solution of 35.3 g. of 2,4-dich1orophenol in '200ml. of acetone. The hydrochloride of compound 4407 is formed, which isisolated by suction filtration after cooling, and it is thenrecrystallised from methanol (yield 61.5 g.) M.P. =l78 C.

The corresponding base is prepared from the hydrochloride by theprocedure described in Example 1. M.P. =130 C. (ethanol).

EXAMPLE Diethylaminoethyl 4-[(4'-chloro 2 methoxy-phenoxy)isobutyrylamino1benzoate (compound 23 or 4553 CB) 33.5 g. of2-diethylaminoethyl para-aminobenzoate dissolved in 170 ml. of acetoneare added to a solution of 35.1 g. of(4-chloro-2-methylphenoxy)isobutyryl chloride in 200 ml. of acetone. Thereaction is exothermic, but the hydrochloride of 4553 CB cannot beobtained in the crys stalline state by cooling, even afterconcentration.

The base is prepared by the procedure described in Example 1. It isobtained in the form of an oil which is treated in solution in acetonewith half the molecular quantity of fumaric acid. The neutral fumarateslowly crystallises. It is separated by suction filtration. M.P. 133 C.The fumarate is recrystallized from absolute ethanol, after which itdoes not change its melting point.

EXAMPLE 6 Diethylaminoethyl4-[(4-allyloxy+phenoxy)isobutyrylamino]benzoate (compound 41 or 4637 CB)10.8 g. of Z-diethylaminoethyl para-aminobenzoate dissolved in 50 ml. ofacetone are added to a solution of 12 g. of (4 allyloxy phenoxy)isobutyryl chloride in 75 ml. of acetone. After the reaction, thesolvent is evaporated and the hydrochloride is decomposed as indicatedin Example 1. The base obtained in this way is then dissolved in acetoneand treated with a stoichiometric quantity of fumaric acid. 22 g. ofacid fumarate are formed (M.P. 142 C.) which are recrystallised fromethanol; it does not undergo any change in melting point.

Compound 58 or 4415 CB may be prepared by the special technique givenbelow.

EXAMPLE 7 Diethylaminoethyl 4-[(4-amino-phenoxy)acetylamino] benzoate(compound 58 or 4415 CB) 2 g. of palladium carbon (5% Pd) are added to asolution of 33.7 g. of compound 57 or 4406 CE in 300 m1. of ethanol andstirred in an atmosphere of hydrogen supplied by a gasometer underatmospheric pressure until absorption of hydrogen is complete. Thetheoretical absorption is obtained in 25 minutes. The catalyst isremoved, the solvent evaporated, the residual oil is dissolved indiethyl ether and a sufficient quantity of a solution of gaseoushydrogen chloride in ether is added for the dihydrochloride toprecipitate. The product is filtered by suction and recrystallised fromethyl alcohol (7.2 g.); the yield of dihydrochloride monohydrate is 45%.M.P.=130 C.

To obtain the base, the hydrochloride is decomposed in aqueous solutionas described in Example 1. The pure base melts at 66 C. aftercrystallization from di-isopropyl ether.

The products set out in Table II have been subjected to various testswhich are described below. They were either used in the form of salts orin the form of the base when that alone was isolated.

(1) Effect on the total fatty acid content of the liver of the white ratsubjected to a protein deficient diet.

Adult male rats weighing 150 to 200 g. are fed with a low protein dietof the following composition (Tucker H., Eckstein H. C., Journal ofBiological Chemistry, 1937, vol. 121, page 479).

Casein 5 Glucose 47.5

Agar-agar 2 Lard 40 Mineral salts 3 Yeast 2 Cystein 0.5

This diet produces widespread fatty degeneration of the liver within 15days, the total fatty acid contents in some cases increasing by morethan compared with control rats receiving a normal diet.

One portion of the animals fed with such a diet is treated from thestart of the test with one of the compounds of the invention at a dailydose of 0.5 millimols/ kg. administered orally (force feeding).

On the fifteenth day of the experiment, the animals are sacrificed andthe total fatty acid content of the liver is determined by thecolorimetric method of Duncomb (Clinica Chimica Acta 1964, vol. 9, page122) and after alkaline hydrolysis and extraction, by the method ofDole, Journal of Clinical Investigation 1956, vol. 35, page 150.

The results are given in values relating to the total fatty acid contentof the liver of the rat.

The value obtained when the control animals receive a normal diet istaken as being equal to O and that obtained when rats receive theprotein deficient diet without treatment is taken as +100.

The results are set out in Table IV.

(2) Effect on the metabolism of Aspergillus niger (SterigmatocystisNigra SN 315).

The effect of the products upon the general metabolism of an organism ina state of dietary excess has been studied on Aspergillus niger(Sterigmatocystis Nigra SN 315). This mould, cultivated in a medium veryrich in carbohydrates, synthesises an increased amount of reserve lipidsand starts to produce exogenic ethanol. The substances to be tested areintroduced at difierent concentrations into the culture medium and theweights of the yields obtained are compared with those of mycellacultivated in an identical medium without the addition.

The production of ethanol and the amount of a-keto glutaric acid andpyruvic acid accumulated in the media are also compared.

(A) Conditions of culture.Culture medium. Each medium consists of 40 ml.of a solution containing, per litre:

G. Glucose 150 Ammonium nitrate 3 Potassium chloride 0.5 Magnesiumsulphate, 7H O 0.5 Monopotassium phosphate 1.0 FeSO -7H O 0.01112 ZnSO-7H O 0.01150 CuSO -5H O 0.00125 MnSO 1H O 0.000845 Ammoniummolybdate-4H O 0.000353 The tests are carried out by introducing thesubstances to be tested at four different concentrations (10- M, 5 10-M, 5 10 M, 5 10- M) into the media.

All the media are sterilized in an autoclave at C. for 20 minutes.

Inoculationn.The mould A. Niger is kept in a tube of carrot medium. Thespores are collected in an intermediate medium of sterile water and theculture media are inoculated by introducing an aliquot portion of thisintermediate medium.

Culture.The culture is prepared in narrow necked ml. flasks for 70 hoursat 34 to 35 C.

Yield.The media are filtered through muslin and the mycelia are washedwith distilled water and then filtered by suction so that the total dryextract can be determined. The medium and the wash waters are made up to100 13 ml. with distilled water, the solution thus obtained serving forthe determination of the ethanol, a-ketoglutaric acid and pyruvic acid.

(B) Methods of determination-Dry extracts.The

mycelia are finely powdered and then placed in an oven.

at 105 C. until the weight is constant (about 7 hours).

Ethanol.-After distillation, the ethanol is determined by oxidation bymeans of nitrochromereagent.

u-Ketoglutaric and pyruvic acid-These acids are quantitatively convertedto their 2,4-dinitrophenylhydrazones and the latter separated by thinlayer chromatography upon silica (development solvent: n-butanolsaturated with 0.5 N ammonia). The intensity of the spots obtained fromdifferent dilutions of the media are compared with the intensity of thespots obtained with difierent quantities of control solutions of thedinitrophenylhydrazones of a-ketoglutaric acid and of pyruvic acid (Rfvalues in the region of 0.10 and 0.35 respectively).

(C) Expression of results.-All the tests are carried out in triplicatefor each concentration of substance being tested. The means of theresults obtained from three tests is compared with the means of theresults obtained from six controls carried out in an identical manner,this means being converted in each case to 100'.

The relative variations within one and the same series (the three testsor six controls) are of the order of 2 :2% for the extracts, :S% for theethanol, i10% for the ketonic acids. The results are set out in TableIV.

Dry extract=dry ext.; ethanol=EtOH; u-ketoglutaric acid=u-keto; pyruvicacid =pyr.

(3) Activating power on the respiration of homogenized brains ofrats.The study is carried out with compound 2842 CB or compound 3compared with Z-diethylaminoethyl para-amino-b'enzoate. The techniqueemployed is that of Warburg. The brains of white rats were ground up anddiluted in Ringers solution.

The table below indicates the results obtained expressed in percents ofincrease of aerobic glycolysis compared with a control period as afunction of the concentration of the products in the product ofhomogenization of brain of rats.

TABLE III Molecular" concentrations 6X10- 5x10 5X10- Compound:

2-diethylaminoethylpara-aminobenzoate 2842 CB (Compound 3) TABLE IVFatty acid rat's liver 2842 or 3.... +43 Dry ext-.. EtOH.-.. a-keto.

Dry ext... EtOH- a-ket0.. Pyr

Dry ext... EtOH- cr-ketO..... Pyr

TABLE IV.Oontinued Fatty acid rat's Asp. 10- 5X10" 5X10- 5X10- N0. liverNiger M M M M 4407 or 11... 28 Dry ext... 47 68 92 100 EtOH...- 125 160130 120 a-keto. 140 180 160 120 Pyr- 200 150 100 100 4485 or 12... 1 +5Dry ext... 1 42 100 105 EtOH.-.- 0 40 115 80 a-ket0 30 120 90 Pyr 200100 70 45 4484 or 13-.- +19 Dry ext... 1 60 95 104 EtO H 0 63 G0 91a-keto. 30 135 73 90 Pyr 170 140 140 110 4499 or 14-.- +1 Dry ext-.. 1 1100 100 E to H- 0 0 80 100 a-keto. 20 20 30 60 Pyr 420 310 400 600 4517or 15 Dry ext- 1 7 93 100 EtOH- 0 20 100 100 a-keto 40 40 120 100 Pyr100 100 100 100 4497 or 16. +10 Dry ext. 53 62 100 100 EtOH.- 135 100100 100 a-keto- 120 120 100 100 Pyr 250 170 140 170 4565 or 17- +74 Dryext... 65 75 95 103 Et0H..-- 110 150 150 105 a-keto. 175 175 65 65 Pyr100 100 50 0 4486 or 21. 6 Dry ext... 100 100 13113011.... 115 110 125100 wketo. 150 120 90 Pyr 280 170 225 4498 or 22. +20 Dry ext-.- 0 45100 100 EtOH.- 0 65 85 a-keto- 55 75 85 Pyr 450 300 100 100 4553 or23... 3 Dry ext... 5 58 98 102 EtO H 0 52 84 93 a-keto- 70 130 100 100Pyr 200 150 100 100 4531 or 24. +62 Dry ext. 1 26 94 97 4621 or 25-.-+23 Dry ext... 1 1 97 100 EtOH 0 0 100 82 a-keto 20 20 60 60 Pyr 200 200100 100 4623 or 26. +12 Dry ext-.- 43 50 97 103 EtOH..-. 64 95 95 70a-keto 150 60 60 Pyr 200 160 100 4521 or 27- +8 Dry ext. 1 1 92 100EtOH.... 0 0 110 110 a-keto 20 20 70 70 Pyr 100 100 100 100 4620 or 31Dry ext- 6 28 85 100 EtOH. 14 33 85 75 a-keto- 65 40 120 120 Pyr 160 160130 100 4405 or 33- 1 Dry ext. 100 100 100 100 EtOH.... 115 100 115 85a-keto 200 85 85 Pyr 100 0 0 0 TABLE IV.-C011ti11ue(l TABLE1V.Conti11uctl Fatty Fatty acid No. N 0. lii ef 4510 or 34 +55 4415 or5s +51 45110r35 +13 Dryext... s5 02 105 100 455201 50". +150 EtOlL 215150 8G 76 a-keto 210 110 130 1 10 Pyr 0 0 0 0 4500 or36..- +53 Dryext... 87 95 106 103 Toxic.

a a s2 PYY 25 0 0 0 From the results given it will be seen that the sub-4628 or 37 +24 Dry mm 5 81 100 100 stances described herein and inparticular compounds 3, EtOH- 3g 5 35 2 23, 31, 48 and 50 may be usedfor therapeutic purposes 0 0 0 0 for the treatment of pathologicalstates relating to lipid 4630 or 0 23 87 100 metabolism. It may, inparticular, be advantageous to 0 15 s2 s7 use these substances 1n: (a)states of hyperlipemia such 8 3 g 8 as familial idiopathic, alimentaryhypercholesterolaemia and hypertriglyceridaemia; and (b) excess tissuelipids as 4519 or g2 g2 1(7)? in atheromatous dyslipaemia, obesity,hepatic steatosis,

120 100 so 40 and tuberous and tendinous xanthomatosis.

0 0 0 0 The dosage may generally vary from 10 to 1500 mg./ 4038 or 40...s4 s4 00 110 day, and administration may be effected by means of 3 2 58tablets, suppositories, preparations for local application 90 00 90 90and ampoules for drinking or injection.

, We claim: 4637 or 28 1% 82 1. A compound selected from the group ofpara- 3 23 3g 38 (phenoxy-acetamido)benzoic acid esters ofdialkylaminoalkanols having the formula 4020 or 42... a3 03 104 95 45 so74 110 7 50 50 50 3;) R4 4522 or 43-.- 1 40 08 100 ,3 a a as 200 130 100100 I i w 4504 or 44-.. 0 84 100 R3 R2 2 a a a 0 0 0 0 in which R ishydrogen, chlorine, a lower alkyl, lower 40270115... +38 g alkenyl,phenyl, benzyl, phenylisopropyl, hydroxyl,

25 25 44 04 alkoxy having up to 6 carbon atoms, allyloxy,cyclopentyloxy, benzyloxy, acetyl, propionyl, nitro, amino or ,1 Dry mm1 1 96 92 sulphamyl group, R is hydrogen, chlorine, lower alkyl,

0 2 or phenyl, R is a hydrogen atom, a lower alkyl, tri- 3 8 8 8fiuoromethyl of methoxy, R is a hydrogen atom or r methyl, X is amethylene group which may be substituted 4614 or 47 EtOH 5 3 2% 3,3 byone or two alkyl groups or by a phenyl group, and

2g 2g 98 8 Y is a group having the formula I 4615 or 48 (1 (1 922 1g?CI1H2I1NR5R6 l 28 28 1% $8 in which n is 2 or 3 and each of R and R is alower alkyl group or R and R taken together with the nitro- 4636 01-50.-12 0 2 79 07 gen atom to which they are attached form a pipeiidino g g9 or morpholino group, provided that when R is chlorine 0 0 0 0 and R isa hydrogen atom the methylene group X has 4639 or 53 +8 0 0 80 92 lessthan two substituents, and the pharmaceutically ac- 0 0 94 92 ceptableacid addition salts of such esters, 8 g g8 $8 2. A compound selectedfrom the group of para- (phenoxyacetamido) benzoic acid esters asclaimed in 4526 +141 F g 8; g? 6? claim 1 in which R is chlorine, R Rand R are hydromkctof 130 130 a gen, X is methylene and Y isdiethylaminoethyl, and 300 200 the hydrochloride thereof. 3. A compoundselected from the group of para- (phenoxyacetamido)benzoic acid estersas claimed in or gigfffi: 8, 33 3 claim 1 in which R is chlorine, R ismethyl, R and R f {28 $38 3 g are hydrogen, X is dimethylmethylene and Yis diethylaminoethyl, and the neutral furnarate thereof. 440601 +46 4.The compound claimed in claim 1 in which R is yphenylisopropyl, R R andR aredtydrogen, X is dimethylmethylene and Y is diethylaminocthyl.

17 18 5. A compound selected from the group of para- References Cited(phenoxyacetamido)benzoic acid esters as claimed in UNITED STATESPATENTS claim 1 in which R is n-pentyloxy, R R and R are hydrogen, X isdimethylmethylene and Y is diethylamino- 3238203 3/1966 Krapcho 260472ethyl, and the acid fumarate thereof- 5 LORRAINE A. WEINBERGER, PrimaryExaminer 6. A compound selected from the group of para-(phenoxyacetamido)benzoic acid esters as claimed in THAXTON AsslstantExammer claim 1 in which R is cyclopentoxy, R R and R are US CLhydrogen, X is dimethylmethylene and Y is diethylaminoethyl and thehydrochloride thereof 10 260247.l, 247.2, 294.3, 470; 424248, 267, 310

